Restenosis is a heart condition that afflicts 35%-50% of all people who undergo balloon angioplasty to improve blood flow in narrowed sclerotic arteries. The condition consists of a significant re-closing of the treated artery segment hours to several months after the procedure. As a result, the arterial lumen size is decreased and the blood flow downstream from the lesion site is impaired. Consequently, patients afflicted with restenosis must undergo an additional balloon angioplasty, and in some cases a coronary bypass surgery must be performed. Aside from pain and suffering of these patients, recurrent stenosis imposes a serious economic burden on society, with estimated restenosis expenses as high as 3.0 billion dollars per year in the United States economy alone.
Attempts to treat restenosis have been concentrated in both the pharmacological and medical device areas. While pharmacological solutions have been proved effective in treating only acute restenosis, a condition developing immediately after balloon angioplasty, some progress has been made with medical devices in the treatment of long term restenosis, a condition developing after a few months following balloon angioplasty. Stents can be inserted into an occluded artery to hold it open. Stents may prevent two of the three mechanisms that cause recurrent stenosis, namely, elastic recoil of the artery and negative remodeling of the arterial structure. The third mechanism, neointimal growth, a proliferation of smooth muscle cells from the lesion into the lumen, is not prevented by stents.
Ionizing radiation holds great promise for treating restenosis. Ionizing radiation serves to damage undesirable hyper-proliferating tissue and ultimately to prevent the hyper-proliferation of cells in the irradiated region. Gamma and beta radiation delivered at the location of stenotic lesions effectively stop both animal and human intimal proliferation. The effective, yet non-hazardous, required dose to treat human restenosis is between seven and forty Gray (mjoule/gram), preferably a dosage greater than fifteen Gray, that penetrates the artery wall at a two mm depth over the lesion length.
Because of the promise that radiation holds for avoiding recurrent restenosis, many methods have been proposed to provide ionizing radiation treatment. These treatment methods may be grouped into three categories: conventional external x-ray irradiation; gamma and beta brachytherapy; and x-ray brachytherapy
External x-ray irradiation cannot treat restenosis safely and effectively. The clinically required doses needed to successfully treat arterial lesions may damage the heart muscle and other organs, due to the non-localized nature of external x-rays. Conventional x-ray radiation for radiotherapy is produced by the following process. High energy electrons are generated and accelerated in a vacuum to impact on a metal target. The sudden deceleration of the high speed electrons into a solid target produces x-rays. Characteristic x-ray radiation results due to a process wherein the bombarding electron ionizes the atom it strikes by removing an electron from one of the atomic orbital shells, leaving a vacancy. An electron from a more remote atomic orbital shell fills this vacancy by jumping to the vacant atomic orbital shell. The consequent release of energy appears as an x-ray photon. Bremsstraalung x-ray radiation is the result of an interaction between a high speed electron and a nucleus. As the electron passes in the vicinity of a nucleus, it suffers a sudden deflection and acceleration. As a result, a part or all of its energy is dissociated from it and propagates in space as an x-ray photon. Conventional x-ray production tubes operate at high voltages, in the range of from 200 kV to 500 kV. However, appreciable x-rays may be produced in x-ray tubes having acceleration voltages as low as 20 kV. The x-ray emission is directly proportional to the electron beam current. However, the efficiency of x-ray generation is independent of electron current, but rather depends on the atomic number of the target material and on the acceleration voltage.
In gamma and beta brachytherapy, a radioactive source is introduced to the treatment site using a special radiation catheter, and the source is placed at this treatment site for a predetermined time, as to deliver the proper radiation dose. Presently, radiation catheters, based on the use of radioactive sources such as beta-emitting .sup.32 P, .sup.90 Sr/.sup.90 Y, .sup.188 W/.sup.188 Re, beta+emitting .sup.48 SV or gamma emitting .sup.192 Ir, are at various stages of development and clinical evaluation. Radioactive stents are also used as alternative delivering means, composed of the above radioactive isotopes.
The gamma and beta radioactive sources used by radiation catheters and radioactive stents have several drawbacks. Their ability to provide selective control of treatment time, radiation dosage, or radiation intensity is limited; and the handling of radioactive materials presents logistical, regulatory, and procedural difficulties. In addition, these devices jeopardize patients by exposing healthy organs to dangerous radiation during the introduction of the radiation source. Hospital personnel that handle radioactive materials are also at risk due to exposure. In addition to the risks these devices impose on patients, hospital staff, and the environment, use of these devices involves a regulatory burden due to the need to comply with nuclear regulatory requirements.
X-ray brachytherapy offers an alternative approach to providing ionizing radiation treatment. In x-ray brachytherapy an internal x-ray emitting miniature energy transducer generates x-rays in-situ. This system offers certain advantages with respect to intra vascular gamma and beta sources. These advantages are, but not limited to, localization of radiation to the treatment site so that the treatment site may be irradiated with minimal damage to surrounding healthy tissue; reduction of hospital personnel risk due to exposure to radioactive materials; and minimization of the regulatory burden that raises from the need to comply with nuclear regulatory requirements.
Another method for the production of x-rays that can possibly contribute to x-ray brachytherapy is direct conversion of light into x-ray radiation. The interaction of light with a target can produce highly energetic x-rays when the power densities achieved are in the range of 10.sup.16 -10.sup.17 watt/cm.sup.2. With the development of the femtosecond laser, such power densities are achievable with moderate size lasers (See C. Tillman et al, NIMS in Phys. Res. A394 (1997), 387-396 and U.S. Pat. No. 5,606,588 issued to Umstadter et al., the contents of each of which are incorporated herein by reference). A 100 femtosecond, one mJ laser pulse focused down to a 3 micron spot, for example, will reach these power density levels.
A variety of medical applications of the direct laser light conversion method of x-ray generation are currently in the development stage. The direct laser light conversion method, for example, has been considered for medical imaging (See, Herrlin K et al. Radiology (USA), vol. 189, no. 1, pp. 65-8, October 1993). Another medical application of femtosecond lasers is in improved non-thermal ablation of neural or eye tissue for surgical purposes (See, F. H. Loesel et al. Appl.Phys.B 66, 121-128 (1998)). The development of compact table top models of femtosecond lasers makes laser generated x-rays an attractive alternative for radiotherapy.
Based on the above, an in-situ radiation treatment apparatus and method has been developed to emit a precisely controlled dose of radiation to a site within a patient's body, such as the interior of an arterial lesion. Co-pending and commonly assigned U.S. Pat. application Ser. No. 09/325,703 filed Jun. 3, 1999, and U.S. patent application Ser. No. 09/434,958 filed Nov. 5, 1999, the contents of which are incorporated herein by reference, describe miniaturized x-ray energy transducers that are coupled to flexible insertion devices to permit in-situ radiation treatment within a human body. The flexible insertion device incorporates optical fibers and/or electrical conductors to supply electrical and/or optical signals to the miniature energy transducer. The miniature energy transducer includes a cathode structure and anode structure spaced apart within a transducer body; and the cathode, anode, and transducer body form a sealed cavity. Electrons are accelerated from the cathode structure to the anode structure and are stopped by the anode to generate x-rays by the application of electrical pulses. The system is capable of delivering a therapeutic radiation dose greater than 15 Gray penetrating 2 mm into an artery wall, without utilizing radioactive materials.
A variety of different types of cathode and anode structures have been proposed for the miniature energy transducer. One proposal utilizes a hollow cathode that includes a cathode shell that defines a cavity. A laser light signal is introduced into the cavity in order to heat an outer surface of the cathode shell, thereby causing thermionic emission of electrons from the outer surface. Another proposal for a hollow cathode incorporates the use of an electron escape nozzle, wherein an electron plasma is generated in the cavity either by applying a light signal to an inner surface of the cathode shell or by providing a spark gap in the cavity of the conducting cathode shell. The electrons exit the cathode shell via the escape nozzle and are accelerated to the anode upon the application of a voltage pulse to the cathode. Still further, in a linear reverse cathode emission type of transducer, an anode is located at a first end of a transducer body and an emission element is located at a second end of the transducer body opposite the anode. The emission element is either a photo-emission electron source or a thermionic emission surface, and it generates electrons when activated by a light source or a high voltage source.
X-ray brachytherapy and radioactive brachytherapy have much in common. However, one main difference between x-ray and radioactive sources is the degree of confidence of the magnitude of the radiation dosage delivered to a treatment site within a patient. In radioactive brachytherapy, the level of activity of the radioactive source can be accurately measured prior to inserting the source into a patient. Once the source is inside the patient's body, it can be expected to maintain the same radiation characteristics during treatment with a very high degree of confidence. While radioactive brachytherapy devices outputs can be accurately predicted, on the other hand x-ray brachytherapy devices require independent verification of emission of radiation while they are operating inside a patient's body. Accordingly, regardless of the type of transducer which is utilized for x-ray brachytherapy, a dosimetry system is needed to measure the cumulative and instantaneous dose of radiation during treatment. PCT Patent Application WO99/45562 and PCT Patent Application WO99/45563 to Chomenky, et al. suggest a system that has a current integration device as a proxy for the dose imparted. The current measurement, however, cannot replace a direct measurement of the x-ray intensity, because x-rays produced are a function not only of the charge passing through the x-ray emitter, but also of the energy the charged electrons have when x-rays are produced. Even if the voltage across the x-ray tube is known, electrons may collide with the transducer walls or with ambient atoms, lose energy, and reach the anode where x-rays are produced with only a fraction of the energy that can be imparted by the voltage difference.
Accordingly, it is an object of the present invention to describe a miniature x-ray transducer with a dosimetry system that measures directly the x-ray intensity produced without relying on proxies such as current and voltage, which may give largely inaccurate results. Another object of the present invention is to provide a dosimetry system protected from electromagnetic noise and cross-talk with high voltages in the x-ray transducer. Furthermore, it is another object of the present invention to provide an energy transducer equipped with a dosimetry system wherein the most preferred embodiment of the dosimeter is as small as possible, so that measurement of the applied dosage may be located at a treatment site within a small blood vessel within the body. Still-further, it is another object of the present invention to provide a system which measures the imparted radiation dosage as a function of time, and then utilizes a feedback loop to enable accurate delivery of the desired dosing profile by controlled variation of the operating parameters of the x-ray transducer.